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C-type Lectin Receptors (CLRs)

C-type lectin receptors (CLRs) are a diverse family of soluble and transmembrane proteins that contain one or more C-type lectin-like domain (CTLD). Multiple members of the CLR family are considered to be pathogen recognition receptors (PRRs) due to their ability to recognize pathogen-associated molecules and induce intracellular signaling pathways that regulate the immune response. Most CLRs that function as PRRs are transmembrane receptors that belong to either the Dectin-1 (Dectin-1, CLEC-1, CLEC-2, CLEC9a, CLEC12B, LOX-1/OLR1, and MICL/CLEC12A) or Dectin-2 (Dectin-2, BDCA-2, CLEC4D/CLECSF8, DCAR, DCIR, and Mincle) subgroups. Many of these receptors are expressed by monocytes/macrophages and dendritic cells, and recognize fucose, mannose, or glucan carbohydrate structures. Signaling pathways activated by CLRs either directly regulate gene expression or modulate TLR signaling. Dectin-1 and Dectin-2 are two well-characterized CLRs that act as PRRs and are primarily expressed by monocytes, macrophages, and dendritic cells. Both receptors have been shown to promote canonical NF-kappa B signaling through activation of spleen tyrosine kinase (SYK) and a multiprotein complex consisting of CARD9, Bcl-10, and MALT1. While Dectin-1 directly interacts with SYK through its cytoplasmic, immunoreceptor tyrosine-based activation motif (ITAM), Dectin-2 interacts with SYK through the ITAM-containing adaptor protein, FcR?. Dectin-1 also regulates NF-kappa B activity through the NIK-dependent, non-canonical NF-kappa B signaling pathway, and through Raf-1-mediated phosphorylation and acetylation. In addition, both Dectin-1 and Dectin-2 activate NFAT and AP-1. As a result, signaling initiated by activation of either receptor can precisely control the expression of numerous cytokines that direct the innate and adaptive immune response. Other CLRs do not directly regulate cytokine expression, but instead modulate TLR-induced signaling pathways. DCIR/CLEC4A, MICL/CLEC12A, and CLEC12B are CLRs that contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) in their cytoplasmic domains. Upon activation, DCIR and MICL recruit the phosphatases, SHP-1 or SHP-2, and inhibit TLR8 or TLR9 signaling by an undefined mechanism. BDCA-2 and DC-SIGN/CD209 do not contain a cytoplasmic ITIM motif, but have also been shown to modulate TLR signaling through alternate pathways. CLRs are particularly important for antifungal immunity. This is highlighted by the fact that targeted deletion of specific CLRs in mice and polymorphisms or mutations in human Dectin-1 or CARD9, respectively, are associated with an increased susceptibility to a variety of fungal pathogens.